Urinary antiseptic



Panel July ,1931

UNITED STATES URINARY AN'rr'sErrrc Floyd De Eds, John 0. Thomas, and Clyde Eddy, San Francisco, Calif.. assiznors to Henry A. Wallace as Secretary of Agriculture of the United States -No Drawing. Application June 22, 1930, Serial No. 30,500

Claims. ((51. 187-.65)

(Granted under the act of March 8, 1883, as

I amended April 30. 1928; 3'10 0. G. 15'!) This application is made under the act of March 3, 1883, as amended by the act of April 30, 1928, and the invention herein described, if

patented, may be manufactured and used by or for the Government for governmental purposes without the payment to us of any royalty thereon.

This invention relates to the use of pheno- 10 thiazine and its oxidation derivatives as antiseptics and more particularly to their use as urinary antiseptics. v

For treatment of-infections of the urinary tract it is desirable that the antiseptic possess the following characteristics:

1. The therapeutic dose should be far below the toxic-margin of safety. v

. Ease of administering. Stability. Ready absorbability.

Non-injurious to digestive tract. Non-destroyable before action. Non-cumulative. Absence of tolerance-development. Ability to act in acid, neutral, or alkaline urine.

Phenothiazine and its three oxidation derivatives, diphenylamine ortho-sulphoxide, mono- 0 oxy-thiodiphenylimid, and dioxythiodiphenylimid meet these requirements. Phenothiazine has the following structural formula:

The following structural formulas are submitted, but the scientific literature is not inaccord regarding the exact structure of the imid compounds:

I l0 monc-oxythiodiphenylamine mono-oxythiodiphenylimid I n I 1 N OH 0- I 15 OH" OH dioxythiodiphcnylamlnc dioxythiodiphcnylixnid N 20 gen Diphcuylamine (ortho)-lulphorido Extensive research conducted on rats, rabbits. and finally on human individuals, after demonstration of the safety of the procedure, have 30 shown that after oral administration of phenothiazine the following results are obtained:

1. Rapid absorption from the digestive tract.

2. Conversion to .one or more of the above oxidation products. 35

3. Excretion of the converted material through the kidneys and into the bladder.

8. Bactericidal properties in acid, neutral, and alkaline urines.

The medicine is administered orally and the dosage may range from a rate of .01 of a gram of'phenothiazine per kilogram of body weight to a maximum of not over .25 of a gram per kilogram of body weight, the period of the dosage not to exceed one week at one time.

When phenothiazine is administered by mouth to rats, rabbits or man, there appears .in the urine dioxythiodiphenylamine and probably also mono-oxythiodiphenylamine, both compounds being excreted in conjugated form. Available evidence shows the compounds to be conjugated as the "sulphates. hydrogen ion concentration of the urine, varying degrees of hydrolysis of the conjugated compounds take place with the liberation of free dioxythiodiphenylamine and mono-oxythiodiphenylamine. Following hydrolysis spontaneous oxidation takes place, the rate of oxidation being dependent upon the pH or hydrogen ion concentration of the urine. As a result of the oxidation of the hydrolyzed products in the urine there is" present dioxythiodiphenylimid and monooxythiodiphenylimid. The proportion of these two compounds is variable and it is highly prob.- able that eventually all the mono-oxythiodlphenylimld is further oxidized to dioxythiodiphenylimid. Therefore, following administration of phenothiazine by mouth urine may contain 'vatying amounts of conjugated mono-oxythiodiphenylamine, conjugated dioxythiodiphenylamine, free mono-oxythiodiphenylamine, free dioxythiodiphenylamine,' and the further oxidation products mono-oxytmodiphenylim'id and'dioxythiodiphenylim-id. The relative amounts of Depending upon the pH orthese compounds present in. the urine is dependent upon the pH or hydrogen ion concentration of the urine and the time elapsed since "voiding of the urine.

Such urines possess bactericidal properties. Whether all 01' the compounds which are present or only one of them is bactericidal has not been determined to date, because a suflicient supply of these diflerent compounds in pure state has not been available for purposes of investigations;

Nevertheless, the fact has been established by addition of bacteria to urine in the test tubefollowing oral administration of phenothiazine, and by the disappearance of bacteria from the urine of rabbits experimentally given cystitis, and'by the disappearance of bacteria in human cases of cystitis. that oral administration of phenothiazine leads to the excretion of a bactericidal urine.

Having fully disclosed our invention we claim:

1. A urinary antiseptic, comprising phenothiazine and its oxidation derivatives as the essential active ingredients.

2. A urinary antiseptic comprising 'diphenylamine-orthosulphoxide as the essential active ingredient.

3. A urinary antiseptic, comprising mono-.oxythiodiphenylimid as the essential active ingredient.

*4. A urinary antiseptic, comprising dioxythiodiphenylimid as the essential active ingredient. 5. A urinary antiseptic comprising phenothiazine as the esesntial active ingredient.

F 10, YD DE EDS. JOHN O. THOMAS. CLYDE W. EDDY. 

